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US 8,710,228 B2Granted
Cycloalkylamine substituted isoquinoline derivatives
AssigneeSanofi
InventorsOliver Plettenburg, Armin Hofmeister, Dieter Kadereit, Stefan Peukert, Sven Ruf, Matthias Löhn, Peter Monecke, Alexander Schiffer, Aimo Kannt, Markus Kohlmann
Life of this patent
Estimating the term…
Abstract
The invention relates to 6-substituted isoquinoline derivatives of the formula (I) useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, and compositions containing such compounds.
Claims46
A compound of the formula (I)
- wherein
- R1 is
- H,
- N[(C1-C6)alkyl]2;
- R2 is H, halogen or (C1-C6)alkyl;
- R3 is
- H,
- halogen,
- (C1-C6)alkyl,
- OH,
- O—R″,
- NH2,
- NHR″,
- NR″R″ or
- NH—C(O)—R″;
- R4 is
- H,
- halogen,
- hydroxy,
- CN,
- (C1-C6)alkyl,
- R5 is
- H,
- halogen,
- CN,
- NO2,
- (C1-C6)alkyl,
- (C2-C6)alkenyl,
- CH(OH)—(C1-C6)alkyl,
- NH2,
- NH—SO2H,
- NH—SO2—(C1-C6)alkyl,
- NH—C(O)—(C1-C6)alkyl,
- C(O)N[(C1-C6)alkyl]2,
- C(O)OH, or
- C(O)O—(C1-C6)alkyl;
- R6 is H, (C1-C6)alkyl or (C1-C6)alkylene-(C3-C8)cycloalkyl;
- R6′ is
- H,
- R′,
- (C1-C8)alkyl,
- (C1-C6)alkylene-R′,
- (C1-C6)alkylene-O—(C1-C6)alkyl,
- (C1-C6)alkylene-O—R′,
- (C1-C6)alkylene-CH[R′]2,
- (C1-C6)alkylene-C(O)—R′,
- (C1-C6)alkylene-C(O)NH2,
- (C1-C6)alkylene-C(O)NH—R′,
- (C1-C6)alkylene-C(O)NH—(C1-C6)alkyl,
- (C1-C6)alkylene-C(O)N[(C1-C6)alkyl]2,
- (C1-C6)alkylene-C(O)N[R′]2;
- (C1-C6)alkylene-C(O)O—(C1-C6)alkyl,
- C(O)O—(C1-C6)alkyl,
- C(O)OR′
- C(O)R′,
- C(O)NH—(C1-C6)alkyl,
- C(O)NHR′,
- C(O)N[(C1-C6)alkyl]R′
- C(O)N[(C1-C6)alkyl]2,
- C(O)—(C1-C6)alkylene-R′,
- C(O)O(C1-C6)alkylene-R′, or
- R6 and R6′, together with the N-atom to which they are attached, form a (C5-C10) heterocyclyl group;
- R7 is
- H,
- halogen,
- CN,
- NO2,
- (C1-C6)alkyl,
- O—(C1-C6)alkyl,
- (C2-C6)alkenyl,
- CH(OH)—(C1-C6)alkyl,
- NH2,
- NH—SO2H,
- NH—SO2—(C1-C6)alkyl,
- SO2—NH2,
- NH—C(O)—(C1-C6)alkyl,
- C(O)N[(C1-C6)alkyl]2,
- C(O)OH, or
- C(O)O—(C1-C6)alkyl;
- R8 is H, halogen or (C1-C6)alkyl;
- n is 1, 2, 3 or 4;
- m is 3;
- and
- L is O or O—(C1-C6)alkylene;
- R′ is
- (C3-C8)cycloalkyl,
- (C5-C10)heterocyclyl,
- (C6-C10)aryl;
- and
- R″ is
- (C5-C10)heterocyclyl,
- (C6-C10)aryl,
- (C1-C6)alkyl,
- (C1-C6)alkylene-O—(C1-C6)alkyl,
- or
- (C1-C6)alkylene-NRxRy;
- and
- Rx and Ry are independently of each other
- (C1-C6)alkyl,
- (C1-C4)alkylene-NH(C1-C6)alkyl, or
- (C1-C4)alkylene-N[(C1-C6)alkyl]2,
- wherein in residues R4, R5, R6, R6′, R7 and R8 as alkyl, alkylene or cycloalkyl can optionally be substituted one or more times by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2;
- wherein in residues R1 to R8 as alkyl or alkylene can optionally be substituted one or more times by halogen;
- wherein in residues R3, R6 and R6′ as (C6-C10)aryl and (C5-C10)heterocyclyl are unsubstituted or substituted one or more times by a group independently selected from halogen, OH, NO2, N3, CN, C(O)—(C1-C6)alkyl, C(O)—(C6-C10)aryl, COOH, COO(C1-6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C3-C8)cycloalkyl, (C1-C6)alkyl, (C1-C6)alkylene-OH, (C1-C6)alkylene-NH2, (C1-C6)alkylene-NH(C1-C6)alkyl, (C1-C6)alkylene-N[(C1-C6)alkyl]2, (C2-C6)alkenyl, (C2-C6)alkynyl, O—(C1-C6)alkyl, O—C(O)—(C1-C6)alkyl, PO3H2, SO3H, SO2—NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2, S—(C1-C6)alkyl;
- SO—(C1-C6)alkyl, SO2—(C1-C6)alkyl, SO2—N═CH—N[(C1-C6)alkyl]2, C(NH)(NH2), NH2, NH—(C1-C6)alkyl, N[(C1-C6)alkyl]2, NH—C(O)—(C1-C6)alkyl, NH—C(O)O—(C1-C6)alkyl, NH—SO2—(C1-C6)alkyl, NH—SO2—(C6-C10)aryl, NH—SO2—(C5-C10)heterocyclyl, N(C1-C6)alkyl-C(O)—(C1-C6)alkyl, N(C1-C6)alkyl-C(O)O—(C1-C6)alkyl, N(C1-C6)alkyl-C(O)—NH—(C1-C6)alkyl], (C6-C10)aryl, (C1-C6)alkylene-(C6-C10)aryl, O—(C6-C10)aryl, O—(C1-C6)alkylene-(C6-C10)aryl, (C5-C10)heterocyclyl, (C1-C6)alkylene-(C5-C10)heterocyclyl, and O—(C1-C6)alkylene-(C5-C10)heterocyclyl, wherein the (C6-C10)aryl or (C5-C10)heterocyclyl in the substituent may be substituted one to three times by a group independently selected from halogen, OH, NO2, CN, O—(C1-C6)alkyl, (C1-C6)alkyl, NH2, NH(C1-C6)alkyl, N[(C1-C6)alkyl]2, SO2CH3, COOH, C(O)O—(C1-C6)alkyl;
- or wherein (C6-C10)aryl is vicinally substituted by a O—(C1-C4)alkylene-O group whereby a 5-8-membered ring is formed together with the carbon atoms the oxygen atoms are attached to;
- and wherein aryl substituent of (C6-C10)aryl and (C5-C10)heterocyclyl substituent groups may not be further substituted by an aryl or heterocyclyl containing group;
- or
- pharmaceutically acceptable salt thereof;
- with the proviso that the following compounds are excluded:
- cis-4-(isoquinolin-6-yloxy)-cyclohexylamine and trans-4-(isoquinolin-6-yloxy)-cyclohexylamine.
108 more elements
A compound selected from the group consisting of;
- trans-[4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester, trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexylamine, [cis-4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester, cis-4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexylamine, cis-4-(4-Chloro-isoquinolin-6-yloxy)-cyclohexylamine, cis-4-(7-Methoxy-isoquinolin-6-yloxy)-cyclohexylamine, trans-4-(5-Bromo-isoquinolin-6-yloxy)-cyclohexylamine, cis-4-(5-Bromo-isoquinolin-6-yloxy)-cyclohexylamine, (3-Fluoro-benzyl)-[cis-4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, [cis-4-(Isoquinolin-6-yloxy)-cyclohexyl]-propyl-amine, [cis-4-(Isoquinolin-6-yloxy)-cyclohexyl]-(3,3,3 -trifluoro-propyl)-amine, [cis-4-(Isoquinolin-6-yloxy)-cyclohexyl]-pyridin-3-ylmethyl-amine, Cyclopropyl-methyl-cis-[4-(isoquinolin-6-yloxy)-cyclo-hexyl]amine, Isobutyl-cis-[4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, Isopropyl-cis-[4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, Cyclopropyl-[4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-dimethyl-amine, Ethyl-[4-(isoquinolin-6-yloxy)-cyclohexyl]-pyridin-4-ylmethyl-amine, Benzyl-[4-(isoquinolin-6-yloxy)-cyclohexyl]-methyl-amine, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-(4-phenoxy-benzyl)-amine, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-[5-(4-methoxy-phenyl)-isoxazol-3-ylmethyl]-amine, N-(4-{[4-(Isoquinolin-6-yloxy)-cyclohexylamino]-methyl}-phenyl)-acetamide, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-(4-methoxy-benzyl)-amine, (4-Chloro-benzyl)-[4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, (2,3 -Dimethoxy-benzyl)- [4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, 5-(4-{[4-(Isoquinolin-6-yloxy)-cyclohexylamino]-methyl}-phenyl)-5-methyl-imidazolidine-2,4-dione, (3,5-Dimethoxy-benzyl)-[4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, 3-{[4-(Isoquinolin-6-yloxy)-cyclohexylamino]-methyl}-benzonitrile, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-(4-methanesulfonyl-benzyl)-amine, [2-(1H-Indol-3-yl)-ethyl]-[4-(isoquinolin-6-yloxy)-cyclohexyl]-methyl-amin, 2-{[4-(Isoquinolin-6-yloxy)-cyclohexyl]-methyl-amino}-N,N-dimethyl-acetamide, 4-[4-(Isoquinolin-6-yloxy)-cyclohexyl]-piperazine-1-carboxylic acid ethyl ester, Isobutyl-[4-(isoquinolin-6-yloxy)-cyclohexy]methyl-amine, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-methyl-pyridin-4-ylmethyl-amine, Ethyl-[4-(isoquinolin-6-yloxy)-cyclohexyl]-(2-methoxy-ethyl)-amine, 4-{[4-(Isoquinolin-6-yloxy)-cyclohexylamino]-methyl}-benzonitrile, 6-(4-Morpholin-4-yl-cyclohexyloxy)-isoquinoline, 4-{[4-(Isoquinolin-6-yloxy)-cyclohexylamino]methyl}-benzoic acid methyl ester, (4-tert-Butyl-benzyl)-[4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, [1-(4-Fluoro-phenyl)-1H-pyrazol-4-ylmethyl]-[4-(isoquinolin-6-yloxy)-cyclohexyl]-methyl-amine, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amine, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-naphthalen-1-ylmethyl-amine, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-(2-phenyl-oxazol-4-ylmethyl)-amine, (2,3 -Dihydro-benzofuran-5-ylmethyl)-[4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-(5-methyl-isoxazol-3-ylmethyl)-amine, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-(2-thiophen-2-yl-thiazol-4-ylmethyl)-amine, (3,5 -Dimethyl-benzyl)-[4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, Biphenyl-2-ylmethyl-[4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-(4-pyrazol-1-yl-benzyl)-amine, [4-(Isoquinolin-6-yloxy)-cyclohexyl]-(4-methoxy-phenyl)-amine, Cyclopropyl-[trans-4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, Cyclopropyl-[cis-4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, [trans-4-(Isoquinolin-6-yloxy)-cyclohexyl]-(4-phenoxy-benzyl)-amine, [cis-4-(Isoquinolin-6-yloxy)-cyclohexyl]-(4-phenoxy-benzyl)-amine, Benzyl-[trans-4-(isoquinolin-6-yloxy)-cyclohexyl]-methyl-amine, Benzyl-[cis-4-(isoquinolin-6-yloxy)-cyclohexyl]-methyl-amine, [trans-4-(Isoquinolin-6-yloxy)-cyclohexyl]-dimethyl-amine, [cis-4-(Isoquinolin-6-yloxy)-cyclohexyl]-dimethyl-amine, N-(4-{[trans-4-(Isoquinolin-6-yloxy)-cyclohexylamino]-methyl}-phenyl)-acetamide, N-(4-{[cis-4-(Isoquinolin-6-yloxy)-cyclohexylamino]-methyl}-phenyl)-acetamide, 2-Chloro-5-{cis[4-(5-chloro-isoquinolin-6-yloxy)-cyclohexylamino]-methyl}-N-dimethylaminomethylene-benzenesulfonamide, 2-Chloro-5-{[-chloro-isoquinolin-6-yloxy)-cyclohexyl amino]-methyl}-benzenesulfonamide, Cyclopropylmethyl-[trans-4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, Bis-cyclopropylmethyl-[trans-4-(isoquinolin-6-yloxy)-cyclohexyl]-amine, [4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-cyclohexyl-amine, [4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-cyclopropyl-amine, [4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-cyclobutyl-amine, [4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-cyclopentyl-amine, [4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-isopropyl-amine, [cis-4-(5-Bromo-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester, cis-4-(5-Ethyl-isoquinolin-6-yloxy)-cyclohexylamine, cis-4-(5-Methyl-isoquinolin-6-yloxy)-cyclohexylamine, cis-4-(5-Vinyl-isoquinolin-6-yloxy)-cyclohexylamine, trans-4-(5,7-Dichloro-isoquinolin-6-yloxy)-cyclohexylamine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester, cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexylamine, cis-4-(5,7-Difluoro-isoquinolin-6-yloxy)-cyclohexylamine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-propyl-amine, Butyl-[cis-4-(7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-amine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-isopropyl-amine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-(1-ethyl-propyl)-amine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-isobutyl-amine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexy]-cyclopropylmethyl-amine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-(3-methyl-butyl)-amine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-cyclohexylmethyl-amine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-cyclohexyl-amine, (4-Chloro-benzyl)-[cis-4-(7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-amine, (3-Chloro-benzyl)-[cis-4-(7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-amine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-(2,4-dichloro-benzyl)-amine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexy]-4-(4-trifluoromethyl-benzyl)-amine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexy]pyridin-4-ylmethyl-amine, [cis-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-ethyl-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-propyl-amine, Butyl-[trans-4-(7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-isopropyl-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-(3-methyl-butyl)-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-cyclohexylmethyl-amine, Benzyl-[trans-4-(7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-(4-methyl-benzyl)-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-pyridin-3-ylmethyl-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-(4-methanesulfonyl-benzyl)-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-naphthalen-1-ylmethyl-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-(tetrahydro-furan-3-ylmethyl)-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-cyclohexyl-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-cyclopropylmethyl-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-isobutyl-amine, (4-Chloro-benzyl)-[trans-4-(7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-amine, (3-Chloro-benzyl)-[trans-4-(7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-(2,4-dichloro-benzyl)-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-(3,5-dichloro-benzyl)-amine, (2-Chloro-benzyl)-[trans-4-(7-chloro-isoquinolin-6-yloxy)-cyclohexyl]-amine, 3-{[trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexylamino]-methyl}-N-[1-dimethylamino-meth-(E)-ylidene]-4-methoxy-benzenesulfonamide, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-4-(4-trifluoromethanesulfonyl-benzyl)-amine, [trans-4-(7-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-4-(4-trifluoromethyl-benzyl)-amine, [6-(cis-4-Amino-cyclohexyloxy)-isoquinolin-3-yl]-(3-methoxy-phenyl)-amine, [6-(cis-4-Amino-cyclohexyloxy)-isoquinolin-3-yl]-(4-methoxy-phenyl)-amine, [6-(cis-4-Amino-cyclohexyloxy)-isoquinolin-3-yl]-(3-chloro-phenyl)-amine, [6-(cis-4-Amino-cyclohexyloxy)-isoquinolin-3-yl]-(4-chloro-phenyl)-amine, [6-(cis-4-Amino-cyclohexyloxy)-isoquinolin-3-yl]-(3,4,5-trimethoxy-phenyl)-amine, [6-(cis-4-Amino-cyclohexyloxy)-isoquinolin-3-yl]-pyrazin-2-yl-amine, and cis-4-(4-Ethyl-isoquinolin-6-yloxy)-cyclohexylamine;
- or a
- pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.